Immunodeficiencies and Autoimmune Diseases: Overview, Clinical Features, and Treatment

1. Immunodeficiencies andautoimmune diseases Martin Liška

2. Immunodeficiencies • Humoral – innate immunity - complement, MBL acquired immunity – immunoglobulins (B lymphocytes) • Cell mediated immunity – innate immunity – phagocytes - acquired immunity – T lymphocytes • Primary – congenital, genetically defined, symptoms predominantly at early age • Secondary – the onset of symptoms at any age chronic diseases effect of irradiation immunosuppression surgical intervention, injuries stress

3. Immunodeficiencies – critical life periods in respect to symptoms onset • Newborn age - severe primary disorders of cell mediated immunity • 6 mth. – 2 yrs. – severe humoral immunodeficiencies cong./transient • 3 - 5 yrs. – transient and selective humoral immunodeficiencies, secondary immunodeficiencies • 15 – 20 yrs. – hormonal instability, thymus involution, life-style changes, some typical infections first symptoms of CVID • Middleage – often excessive workload, stress first symptoms of autoimmune disorders (also immunodeficiency) • Advanced and old age – rather symptoms of severe secondary immunodeficiencies, repercussion of functional disorders

4. Immunodeficiencies – major clinical features • Antibodies - microbial infections (capsulated bacteria) respiratory - pneumonia, sinusitis, otitis GIT – diarrhea • Complement system – microbial infections (pyogenic), sepsis edema (HAE) – C1-INH deficiency • T cells - bacterial, fungal, viral infections GIT – diarrhoea respiratory – pneumonia, sinusitis • Phagocytes - abscesses, recurrent purulent skin infections granulomatous inflammation

5. I. Primary immunodeficiencies – defectsofphagocytosis 1/ Quantitative – decreased numbers of granulocytes Congenital chronic agranulocytosis Cyclic agranulocytosis (neutropenia)

6. I. Primary immunodeficiencies – defectsofphagocytosis 2/ Qualitative – phagocytes functional disorders, various enzyme deficits, inability of phagocytes to degrade the ingested material Chronic Granulomatous Disease (CGD) • Approximately in 60% X-linked, some forms AR • Enzymatic inability to generate toxic oxygen metabolites (H2O2) during oxygen consumption) - defect in neutrophilic cytochrome b (part of complex containing NADPH oxidase) • Inability to kill catalase producing bacteria such as Staph.aureus, Pseud.aeruginosa • Clinical features: granulomas of skin, organs • Treatment: long-term ATB prophylaxis, in more severe cases BMT

7. II. Primary immunodeficiencies –complementsystemdisorders Hereditary angioedema(HAE) • Absence orfunctional defect of C1-inhibitor • Recurrent swellings of skin or mucosa (oropharynx, gut) triggered by intercurrent infect, trauma or surgery • Uncontroled activation of kinin system • Laryngeal edemas could be life-threatening, immediate treatment is necessary • Treatment:preventive – androgens, EACA, C1 inhibitor concentrate rescue -administration of C1 concentrate (or recombinantly produced) - administration of bradykinin receptor antagonist (icatibant)

8. III. Primary immunodeficiencies – antibodydeficiencies X-linked hypogamaglobulinemia (XLA, Bruton’s agammaglobulinemia) • Most common X-linked form • Block of maturation of pre-B cells into B cells (Bruton’s tyrosine kinase defect) • Undetectable or very low serum levels of Ig, absence of B cells • Symptoms: pneumonias, pyogenic otitis, increased occurrence of pulmonary fibrosis • Treatment: life-long Ig replacement CVID – Common Variable ImmunoDeficiency • Heterogenous group of B cell functional defects • Low levels of IgG and IgA, B cell counts normal • Symptoms: onset mostly between 2nd and 3rd decade recurrent respiratory tract infections (pneumonia, sinusitis) • Treatment: life-long Ig replacement

9. III. Primary immunodeficiencies – antibodydeficiencies Selective IgA deficiency • Disorder of B cell function: absence of IgA, levels of the other Ig normal • Recurrent mild/moderate infections or asymptomatic • Risk of reaction to live attenuated vaccines or generation of anti-IgA antibodies after blood transfusion Selective IgG subclasses deficiency, specific IgG deficiency • B cell functional disorder • Onset of symptoms in childhood, mostly respiratory tract infections caused by encapsulated bacteria (H.influenzae, Pneumococci) Transitory hypogammaglobulinemia of infancy • Milder and transitory decrease of IgG and IgA

10. IV. Primary immunodeficiencies –combined T and B cell disorders diGeorge syndrome • Disorder of development of 3rd and 4th branchial pouch → congenital heart disease + absence of thymus + absence of parathyroid glands • Complete or parcial • Symptoms: symptoms of cong.heart dis. – prominent immunodeficency – variable (mild functional → absence of T cells) hypocalcemic spasms – possible mental deficit • Treatment: symptomatic, in complete form BMT

11. IV. Primary immunodeficiencies –combined T and B cell disorders SCID – Severe Combined ImmunoDeficiency • X-linked recessive or AR disease, combined disorder of humoral and cell mediated immunity • Severe disorder (patients often die during until 2nd year of age), onset of symptoms soon after birth (severe diarrhoea, pneumonia, meningitis, BCGitis) • Immunological features: typically lymphopenia, absence of T cells, hypogammaglobulinemia • Forms:X-linked form – the most common, T-B+NK-, defect of common gamma chain shared by receptors of various important cytokines → absence of T cells AR form – T-B-, enzymatic defect (ADA, PNP) → accumulation of metabolites toxic for DNA synthesis → lymphopenia Ommen sy. - defect of recombinases → defect of VDJ recombination → proliferation of one or more clones of autoreactive T cells • Treatment: BMT is of critical significance, in ADA deficiency gene therapy ATB, IVIG

12. V. Primary immunodeficiencies - immunodeficiency with immune dysregulation X-linked lymphoproliferative syndrome (XLP) • Abnormal immune response to EBV infection which leads to uncontroledlymphoproliferation • Disorder of gene localized on X chromosome - mutation of gene coding protein associated with signal activating molecule of lymphocytes SLAM (SAP) or inhibitor of apoptosis (XIAP) • Development of uncontroledlymphoproliferation and NK cell disorder • EBV infection with fulminant or fatal course leading to liver failure → surviving patients are at risk of B cell lymphoma development, hypogammaglobulinemia similar to CVID or aplasticanemia • Without BMT performed before EBV infection development, XLP is fatal sooner or later

13. VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency HyperIgEsyndrome (HIES, Job’s syndrome) • Eczema + combined immunodeficiency manifesting by recurrent abscesses (cold abscesses) + recurrent sinopulmonary infections • More common AD form caused by mutation of STAT3 gene (Signal Transducer and Activator of Transcription 3), less common AR form caused by mutation of DOCK8 gene (Dedicator Of CytoKinesis 8) Symptoms: onset frequently in infancy recurrent staphylococcal abscesses of skin, lungs, joints or internal organs recurrent sinopulmonary infections, pneumatocele severe atopic eczema in AD form: skeletal disorders (facial asymmetry, prominent forehead, broad nasal bridge, spontaneous bone fractures, osteopenia), delayed dental erruption

14. VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency HyperIgEsyndrome (HIES, Job’s syndrome) Symptoms: in AR form, recurrent viral infections (herpetic), increased frequency of autoimmune or allergic diseases, skeletal disorders often absent Dg: clinical features enormously increased level of serum IgE (˃ 2000 IU/ml) genetic tests Th: prophylaxis with anti-staphylococcal ATB dermatological therapy of eczema surgical treatment of abscesses

15. VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency Wiskott-Aldrich syndrome (WAS) • X-linked recessive disease • Decreased number of small platelets (microthrombocytopenia), eczema and immunodeficiency • Mutation of WASp gene → decreased production of WASp protein (exprimed on hematopoietic cells, provides dynamic changes of cytoskeleton which are necessary for function of immune cells) Symptoms: combined immunodeficiency: decreased Ig levels (↓IgM; ↑IgA and IgE) + defects of T cell function → recurrent otitis and sinusitis, autoimmune diseases thrombocytopenia → increased bleeding

16. VI. Primary immunodeficiencies –well-defined syndromes with immunodeficiency Wiskott-Aldrich syndrome (WAS) Dg: clinical symptoms proof of decreased expression of WASp on leukocytes genetic tests Th: symptomatic treatment in case of matched donor BMT studies of gene therapy

17. Immunoglobulin replacement therapy • Immunoglobulin concentrates are made from human plasma pooled from thousands of donors • Donors are tested for infectious diseases (HIV, hepatitis), inactivating procedures to minimize the risk of transmitting infection • Ig concentrates contain only IgG, content of IgA is minimal • Preparates for i.v. (Gammagard, Octagam) or s.c. administration (Subcuvia, Gammanorm)

18. Indications for Ig replacement therapy • Primary antibody deficiencies (IVIG) – life-long in XLA or CVID, transitory in combined immunodeficiencies (SCID) • IgG subclasses or specific Ig deficiency is sometimes also indication • Secondary antibody deficiencies – typically B cell leukemia, lymphoms

19. Dosage of Ig concentrates • Agammaglobulinemia – i.v. imunoglobulins 400-600 mg/kg/month • Regular administration in day-care centres every 3 or 4 weeks • Last years, „home therapy“ is frequently used - administration of subcutaneous Ig by infusion pump (cca every 5 to 7 days, more comfortable for patient, less adverse effects)

20. Secondary immunodeficiencies • Acute and chronic viral infections – infectious mononucleosis, influenza • Metabolic disorders– diabetes mellitus, uremia • Autoimmune diseases– autoantibodies against immunocompetent cells (neutrophils, lymphocytes); autoimmune phenomena also after administrationof certain drugs (e.g. oxacilin, quinidine) • ChronicGIT diseases • Malignant diseases(leukemia) • Hypersplenism/asplenia • Burn, postoperative status, injuries • Severe nutritional disorders • Chronic infections • Ionizing radiation • Drug induced immunodeficiencies(chemotherapy) • Immunosupressive therapy • Chronic stress • Chronic exposureto harmfulchemical substances

21. AcquiredImmunoDeficiency Syndrome (A.I.D.S.) • Caused by retrovirus HIV 1 or HIV 2 • Virus has a tropism for cells bearing CD4 surface marker (Th CD4+ lymphocytes); also infects macrophages and CNS cells • Viral genome transcribes into human DNA and infected cell provides viral replication • Diagnosis: serological (3 to 6 weeks after primoinfection, PCR • Transmission: sexual contact contact with blood or blood products mother-to-child – prenatally, delivery, breast feeding • Phases: acute (flu-like symptoms) asymptomatic – months to years, viral replication, loss of Th cells symptomatic – infections, autoimmune disorders, malignancies, allergy final – systemic breakdown, opportune infections (Pneumocystis jirovecii, Cryptococcus neoformans, Toxoplasma gondii, Candida albicans, CMV etc.) - Kaposi’s sarcoma

22. Acquired ImmunoDeficiency Syndrome (A.I.D.S.) Diagnosis: • Serology - specific antibodies, 4 to 12 weeks after primoinfection • Measurement of antigen p24 – before seroconversion • Viral RNA measurement – before seroconversion, PCR testing • Th cells counts Therapy: - HAART (Highly Active Antiretroviral Therapy) – combination of nucleoside (Zidovudine) and non-nucleoside (Nevirapin) reverse transcriptase inhibitors and protease inhibitors (Lopinavir)

23. Acquired ImmunoDeficiency Syndrome (A.I.D.S.) Therapy: • Prophylaxis with antibiotics and antimycotics • TBC prevention (isoniazid) • Ig replacement

24. AUTOIMMUNE DISEASES

25. Autoimmune disease • Results from a failure of self-tolerance • Immunological tolerance is specific unresponsiveness to an antigen • All individuals are tolerant of their own (self) antigens

26. AUTOIMMUNE PATOLOGICAL RESPONSE- ETIOLOGY • the diseases are chronic and usually irreversible • incidence: 5%-7% of population, higher frequencies in women, increases with age • factors contribute to autoimmunity: - internal (HLA association, polymorphism of cytokine genes, defect in genes regulating apoptosis, polymorphism in genes for TCR a H immunoglobulin chains, association with immunodeficiency, hormonal factors) - external (infection, stress by activation of neuroendocrine axis and hormonal dysbalance, drug and ionization through modification of autoantigens)

27. CLINICAL CATEGORIES • systemic - affect many organs and tissue • organoleptic - affect predominantly one organ accompanied by affection of other organs (inflammatory bowel diseases, celiac disease, AI hepatitis, pulmonary fibrosis) • organ specific - affect one organ or group of organs connected withdevelopment or function

28. SYSTEMIC AUTOIMMUNE DISEASES • Systemic lupus erythematosus • Rheumathoid arthritis • Sjögren‘s syndrome • Dermatopolymyositis • Systemic sclerosis • Mixed connective tissue disease • Vasculitis

29. SYSTEMIC LUPUS ERYTHEMATOSUS • chronic, inflammatory, multiorgan disorder • autoantibodies react with nuclear material and attack cell function, immune complexes with dsDNA deposit in the tissue • general symptoms: include malaise, fever, weight loss • multiple tissueare involved including the skin, mucosa, kidney, joints, brain and cardiovascular system • characteristic features: butterfly rash, renal involvement, CNS manifestation, pulmonary fibrosis

30. DIAGNOSTIC TESTS • a elevated ESR (erythrocyte sedimentation rate), low CRP, trombocytopenia, leucopenia, hemolytic anemia, decreased levels of complement compounds(C4, C3), elevated serum Ig levels, immune complexes in serum

31. AUTOANTIBODIES • Autoantibodies: ANA, dsDNA (double-stranded), ENA (SS-A/Ro, SS-A/La), Sm, against histones, phospholipids

32. RHEUMATOID ARTHRITIS • chronic, inflammatory disease with systemic involvement • characterized by an inflammatory joint lesion in the synovial membrane, destruction of the cartilage and bone, results in the joint deformation • clinical features: arthritis, fever, fatigue, weakness, weight loss • systemic features: vasculitis, pericarditis, uveitis, nodules under skin, intersticial pulmonary fibrosis • diagnostic tests: elevated C- reactive protein and ESR, elevated serum gammaglobulin levels - autoantibodies against IgG = rheumatoid factor (RF), a-CCP (cyclic citrulline peptid), ANA - X-rays of hands and legs- show a periarticular porosis, marginal erosion

33. SJÖGREN‘S SYNDROME • chronic inflammatory disease affecting exocrine glands • the primary targetsare the lacrimal and salivary gland duct epithelium • general features: malaise, weakness, fever • primary syndrome - features: dry eyes and dry mouth, swollen salivary glands, dryness of the nose, larynx, bronchi and vaginal mucosa, involvement kidney, central and periferal nervous system, arthritis • secondary syndrome – is associated with others AI diseases (SLE, RA, sclerodermia, polymyositis, primary biliary cirhosis,AI thyroiditis) • autoantibodies against ENA (SS-A, SS-B), ANA, RF • The Schirmer test - measures the production of tears

34. Vasculitis • characterized by inflammatory destruction of vessels leading to thrombosis and aneurysms • proliferation of the intimal part of blood-vessel wall and fibrinoid necrosis • affect mostly lung, kidneys, skin • diagnostic tests: elevated ESR, CRP, leucocytosis, biopsy of affected organ (necrosis, granulomas), angiography

35. Vasculitis • p- ANCA (myeloperoxidase) positivity (Polyarteritis nodosa, Churg- Strauss, Microscopic polyarteritis nodosa) • c- ANCA (serin proteinase) positive (Wegener granulomatosis, Churg- Strauss syndrome)

36. Vasculitis - classification • Large vessel vasculitis (Takayasu arteritis, Giant cell (temporal) arteritis) • Medium vessel vasculitis (Polyarteritis nodosa, Wegener's granulomatosis, Kawasaki disease) • Small vessel vasculitis (Churg-Strauss arteritis, Microscopic polyarteritis, Henoch-Schönlein purpura) • Symptoms: fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction

37. ORGANOLEPTIC AUTOIMMUNE DISEASES • Ulcerative colitis • Crohn‘s disease • Autoimmune hepatitis • Primary biliary cirhosis • Pulmonary fibrosis

38. Ulcerative colitis • chronic inflammation of the large intestine mucosa and submucosa • features: diarrhea, bloody and mucus stools • extraintestinal features (arthritis, uveitis) • Autoantibodies:pANCA, a- large intestine

39. Crohn‘s disease • the granulomatous inflammation of whole intestinal wall with ulceration and scarring that can result in abscess and fistula formation • the inflammation of Crohn's disease the most commonly affects the terminal ileum, presents with diarrhea and is accompanied by extraintestinal features - iridocyclitis, uveitis, artritis, spondylitis • antibodies againstSaccharomyces cerevisiae (ASCA), a- pancreas

40. AUTOIMMUNE ENDOCRINOPATHY • Hashimoto‘s thyroiditis • Graves-Basedow disease • Diabetes mellitus I. type • Addison‘s disease • Autoimmune polyglandular syndrome

41. Hashimoto‘s thyroiditis • thyroid disease result to hypothyroidism on the base of lymphocytes and plasma cells infiltrate • autoantibodies against thyroidal peroxidase (a-TPO) and/or against thyroglobulin (a-TG)

42. Grave‘s disease • thyrotoxicosis from overproduction of thyroid hormone (patient exhibit fatigue, nervousness, increased sweating, palpitations, weight loss, exophtalmus) • autoantibodies against thyrotropinreceptor, autoantibodies cause thyroid cells proliferation

43. Diabetes mellitus (insulin- dependent) • characterized by an inability to process sugars in the diet, due to a decrease in or total absence of insulin production • results from immunologic destruction of the insuline- producing β-cells of the islets of Langerhans in the pancreas • autoantibodies against GAD(glutamic acid decarboxylase = primary antigen), autoantibodies anti- islet cell, anti- insulin • islets are infiltrated with B and T cells

44. AUTOIMMUNE NEUROPATHY • Guillain-Barré syndrome (acute idiopathic polyneuritis) • Myasthenia gravis • Multiple sclerosis

45. Multiple sclerosis • chronic demyelinizing disease with abnormal reaction T cells to myeline protein on the base of mimicry between a virus and myeline protein • features: weakness, ataxia, impaired vision, urinary bladder dysfunction, paresthesias, mental abberations • autoantibodies against MOG (myelin-oligodendrocyte glycoprotein) • Magnetic resonance imaging of the brain and spine shows areas of demyelination • The cerebrospinal fluid is tested for oligoclonal bands, can provide evidence of chronic inflammation of the central nervous system

46. AUTOIMMUNE CYTOPENIA • AI hemolytic disease- autoantibodies against membrane erythrocyte antigens • AI trombocytopenia - autoantibodies against trombocyte antigens (GPIIb/IIIa) • AI neutropenia - autoantibodies against membrane neutrofil antigens

47. Treatment of autoimmune diseases Systemic AI – non-specific immunosuppression: glucocorticoids cytostatics: • alkylating agents- cyclophosphamide • purine analogs - azathioprine, mycophenolate, • antimetabolites - metotrexate • antibiotics - cyclosporin A, tacrolimus • monoclonal antibodies Organ specific AI - non-specific immunosuppression Endocrinopathies - Substitution of lacking product of endocrinal gland destroyed by AI process • insulin, thyroid gland hormones